Interleukin-4 (IL-4) and Interleukin-13 (IL-13) are cytokines involved in several inflammatory diseases caused by immune dysregulation, most notably asthma and atopic dermatitis. Studies conducted with animals deficient in either cytokine, or employing reagents that neutralize either IL-4 or IL-13 function, have elucidated the important role these cytokines play in regulating the primary and secondary immune response leading to airway inflammation and airway hyper-responsiveness (Zhu et al. 1999. J. Clin. Invest. 103: 779-788, Henderson et al. 2000 J. Immunol. 164: 1086-1095). Cumulatively, these data suggest that IL-4 and IL-13 have overlapping as well as independent roles in the allergic airways response.
IL-4 is increasingly appreciated as the pivotal cytokine initiating the “Th2-type” inflammatory response forming the underling milieu necessary for the development of atopy and asthma. IL-4 effects include activation, proliferation and differentiation of T and B cells. During proliferation of B-lymphocytes, IL-4 acts as a differentiation factor by regulating class switching from IgG to the IgE, thus encouraging the development of allergic reactions.
IL-13 is now appreciated as the more probable downstream effector cytokine. IL-13 dominate effects include induction of airways hyperresponsiveness (AHR) and goblet cell hyperplasia, both cardinal features of asthma. However, there is considerable redundancy in the effects of these two cytokines. The redundancy in effects associated with the binding and signaling of these two cytokines can be explained by their sharing of common receptors.
The IL-4 receptor alpha chain (IL-4Ra) is known to form two distinct ternary complexes with ligands and coreceptors. The type I receptor complex (IL-4R) is typically formed in lymphoid cells and consists of the IL-4Ra chain and the IL-2 receptor common gamma chain (IL-2Rg). It binds specifically to and transduces signals by the IL-4 cytokine ligand. In nonlymphoid cells, e.g. airway epithelial cells, IL-4R alpha chain forms a complex with the IL-13 receptor alpha chain 1(IL-13Ra1). This so called type II receptor (also called IL-13R) binds to and is activated by both IL-4 and IL-13.
The receptor chains (IL-4Ra, IL-13Ra1 and IL-2Rg) interact specifically with downstream nonreceptor tyrosine kinases of the Janus kinase (Jak) family, with the IL-4Ra associating with Jak1, the IL-2Rg chain with Jak3, and the IL-13Ra chain with Tyk2. Upon ligand binding to the receptor, these kinases are activated by an as yet not understood mechanism, and cause phosphorylation of the receptor chains, the kinases themselves, and eventually of the transcription factors of the Stat family that are recruited to the phosphorylated receptors.
While asthma is generally defined as an inflammatory disorder of the airways, clinical symptoms arise from intermittent air flow obstruction. It is a chronic disabling disorder that appears to be increasing in prevalence and severity. It is estimated that 30-40% of the population suffers with atopy, and 15% of children and 5% to 10% of adults in the population suffer from asthma.
Atopy or atopic syndrome is a predisposition toward developing certain allergic hypersensitivity reactions. A patient with atopy typically presents with one or more of the following: eczema (atopic dermatitis or neurodermatitis), allergic rhinitis (hayfever), allergic conjunctivitis, or allergic asthma. Patients with atopy also have a tendency to have food allergies.
Current treatments for these diseases involve interference with downstream effector molecules such as anti-IgE as well as immune suppressing agents (i.e. corticosteroids). However, these approaches are not efficient in all patients and are associated with, often severe, side effects.
Beta agonists reduce the symptoms of asthma, i.e. transiently improve pulmonary functions, but do not affect the underlying inflammation so that lung tissue remains in jeopardy. In addition, constant use of beta agonists results in desensitization, which reduces their efficacy and safety. The agents that can diminish the underlying inflammation, the anti-inflammatory steroids, have their own known list of disadvantages that range from immunosuppression to bone loss.
Because of the problems associated with conventional therapies, alternative treatment strategies have been evaluated. Glycophorin A, cyclosporin, and a non-peptide fragment of IL-2, all inhibit interleukin-2 dependent T lymphocyte proliferation and, therefore, IL-9 production; however, they are known to have many other effects. While these agents may represent alternatives to steroids in the treatment of asthmatics (Zav'yalov et al. 1992. Immunol. Lett. 31:285-288 56), they inhibit interleukin-2 dependent T lymphocyte proliferation and potentially critical immune functions associated with homeostasis.
It is known that a dynamin dependent, clathrin independent pathway is responsible for the clearance of IL-2beta receptor following ligand binding, and that this pathway is dependent upon the activity of the small G proteins RhoA and Rac1, and the kinases PAK1 and PAK2 (Grassart A et al. 2008 EMBO Rep. 9(4):356-62). Rac and PAK family kinases are further known to play a role in macropinocytosis and type I phagocytosis, i.e. internalization of immunoglobulin activated Fe-receptors (Qualmann B, Mellor H 2003, Biochem J 371, 233-241), EphrinB receptors (Marston D j et al. 2003. Nature Cell Biology 5, 879-888), and cadherins (Yap A S et al. 2007. Current Opinion in Cell Biology 19:508-514). It is known that PAK promotes morphological changes by acting downstream of Rac (Oelschlager, T. A. et al 1993 EMBO J. 17:4328-4339).
US2002/045564A1 relates to a method of modulating smooth Muscle contraction, comprising administering a PAK3 modulating agent to a subject such that modulation of smooth muscle contraction occurs.
US 2003/0165992A relates to a method for detecting a predisposition to asthma or atopy in an individual, the method comprising: analyzing a biological specimen from said individual for the presence of a Il-13 Gln110Arg variant; wherein the presence of said variant is indicative of an increased susceptibility to asthma or atopy.
US2007/0212308A relates to a method of treating asthma comprising administering to a subject in need thereof, a pharmaceutical composition containing a therapeutically effective amount of a mutant human IL-4 protein.
U.S. Pat. No. 7,635,754 discloses a chimeric polypeptide, comprising an interleukin-4 (IL-4) mutein receptor antagonist operatively linked to an interleukin-9 (IL-9) mutein receptor antagonist and wherein the chimeric polypeptide reduces or inhibits the association of an interleukin with an IL-4 receptor, an IL-9 receptor, an interleukin-13 (IL-13) receptor, or a combination thereof, in particular for the treatment of asthma.
What is needed in the art is the identification of a pathway critical to the development of asthma and atopy that allows the development of novel therapeutic approaches. The objective of the invention is further to provide agents for the treatment of asthma and atopy.